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Synthesis of a BACE1 Inhibitor
Efficient Method for the Synthesis of Amino-1,3-Oxazines from Thioureas.
Org. Process Res. Dev. 2020;
Key wordsBACE1 inhibitor - Alzheimer’s disease - thioureas - 2-amino-1,3-oxazines - N-arylation - copper(I) iodide
The target molecule L, an inhibitor of the β-amyloid cleaving enzyme 1 (BACE1), is of interest for the treatment of Alzheimer’s disease. A synthesis of L was recently disclosed (US 2019 0106434 A1) that features the reaction of N-benzoyl thiourea G with TMSCl in DMSO at 10 °C to give 2-amino-1,3-oxazine I in 96% yield. Eight simpler examples of the cyclization reaction are described.
The key cyclization reaction G → H can be performed by reacting either TMSCl or HCl with DMSO to form sulfonium salts, which can activate the thiourea, enabling the elimination of dimethyl sulfide and sulfur to form a carbodiimide intermediate, which cyclizes to form the 2-amino-1,3-oxazine. The overall yield for the 18-step synthesis is 7.5%
16 February 2021 (online)
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